N-Carboxymethyl(amidino)lysyl-proline antihypertensive agents

Claim 2

Compounds of the formulae: and wherein: R and R 2 are independently hydrogen; loweralkyl: aralkyl; or aryl; R 1 is hydrogen; branched or straight chain C 1-12 alkyl and alkenyl; C 3 -C 9 cycloalkyl and benzofused alkyl; substituted loweralkyl where the substituents are halo, hydroxy loweralkoxy, aryloxy, amino, mono- or diloweralkylamino, acylamino, arylamino, guanidino, mercapto, loweralkylthio, arylthio, carboxy, carboxamido, or loweralkoxycarbonyl; aryl; substituted aryl where the substituents are loweralkyl, loweralkoxy, or halo; arloweralkyl; arloweralkenyl: heteroarloweralkyl; heteroarloweralkenyl; substituted arloweralkvl, substituted arloweralkenyl, substituted heteroarloweralkyl, or substituted heteroarloweralkenyl where the aryl and heteroaryl substituents are halo, dihalo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl, acylamino, mono- or diloweralkylamino, carboxyl, haloloweralkyl, nitro, cyano, or sulfonamido, and where the loweralkyl portion of arloweralkyl may ue substituted by amino, acylamino, or hydroxyl; or where X and Y taken together are -CH 2 -CH 2 -; R 4 is hydrogen- loweralkyl; aryl- substituted aryl R 5 is hydrogen; loweralkyl; aryl- or substituted ary n is 1 to 3; W is absent; -CH 2 -; or Z is where m is 0 to 2, provided that m may not be 0 and W may not be absent at the same time; and R 6 is hydrogen; loweralkyl; halo; or OR 4 ; R 2 is. where r and s are independently 0 to 3: B is absent; -O-; -S-; or -NR 8 -; where R 8 is hydrogen; loweralkyl; alkanoyl; or aroyl; and R 7 is where R 9 is loweralkyl: aralkyl; aryl; heteroaryl; or heteroarloweralkyl and these groups substituted by hydroxy, lower alkoxy or halo; carboxyl; carboxamido; nitromethenyl. R 10 is hydrogen; loweralkyl; aryl; or amidino; R 11 is hydrogen; loweralkyl- cyano; amidino; aryl; aroyl; loweralkanoyl; -NO 2 ; -SO 2 NH 2 ; or SO 2 R 13 ; R 12 is hydrogen; loweralkyl; halo; aralkyl; amino: cyano; mono-or diloweralkylamino; or OR 4 ; R 13 is hydrogen; loweralkyl; or aryl; R 15 is hydrogen; lower alkyl; aralkyl; or aryl. constitute a bas.ic heterocycle of 5 or 6 atoms or benzofused analogs thereof and optionally containing 1-3 N atoms, an oxygen, a sulfur, an S=O, or an SO 2 group optionally substituted by amino, lower alkyl amino, diloweralkyl amino, lower alkoxy, or aralkyl groups; R3 is C 3-8 cycloalkyl and benzofused C 3-8 cycloalkyl; perhydrobenzofused C 3-8 cycloalkyl; aryl; substituted aryl; heteroaryl; substituted heteroaryl; R14 is hydrogen or loweralkyl; and, a pharmaceutically acceptable salt thereof.

Claim 3

A compound of Claim 1 which is a member of the group: N 2 -[1-(S)-carboxy-3-phenylpropyl]-N 6 -(4,5-dihydro-2-thiazolyl)-L-lysyl-L-proline: N 2 -[1-(S)-carhoxy-3-phenylpropyl]-N 6 -(1-imino- phenyl)-L-lysyl-L-proline; N 2 -[1-(S)-carboxy-3-phenylpropyl]-ω-nitro-L-arginyl-L-proline- N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -[(cyanoamino)-iminomethyl]-L-lysyl-L-proline; N 2 -[1-(S)-carboxy-3-phenylpropyl]-N 6 -[[(amino- iminomethyl)amino]iminomethyl]-L-lysyl-L-proline; N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -(2-pyrimidinyl)-L-lysyl-L-proline; N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 5 -(2-benzothiazolyl)-L-ornithyl-L-proline; and, N 2 [1-(S)-carboxy-3-phenylpropyl]-ω-carbamoyl-L-arginyl-L-proline.

Claim 4

A pharmaceutical composition useful in treating hypertension comprising a pharmaceutically acceptable carrier and an antihypertensively effective amount of a compound of the formulae: and wherein: R and R 2 are independently hydrogen- loweralkyl; aralkyl; or aryl: R 1 is hydrogen; branched or straight chain S 1-12 alkyl and alkenyl; C3 -C 9 cycloalkyl and benzofused alkyl; substituted loweralkyl where the substituents re halo. hydroxy loweralkoxy, aryloxy, amino, mono- or diloweralkylamino, acylamino, arylamino, guanidino, mercapto, loweralkylthio, arylthio, carboxy, carboxamido, or loweralkoxycarbonyl; aryl. substituted aryl where the substituents are loweralkyl, loweralkoxy, or halo; arloweralkyl; arloweralkenyl; heteroarloweralkyl; heteroarloweralkenyl; substituted arloweralkyl, substituted arloweralkenyl, substituted heteroarloweralkyl, or substituted heteroarloweralkenyl where the aryl and heteroaryl substituents are halo, dihalo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl, acylamino, mono- or diloweralkylamino, carboxyl, haloloweralkyl, nitro, cyano, or sulfonamido, and where the loweralkyl portion of arloweralkyl may be substituted by amino, acylamino, or hydroxyl; or where X and Y taken together are CH 2 -CH 2 ; R 4 is hydrogen; loweralkyl aryl; substituted aryl, R 5 is hydrogen; loweralkyl; aryl; or substituted aryl. n is 1 to 3; W is absent; -CH 2 -; or Z is where m is 0 to 2, provided that m may not be 0 and W may not be: absent .at the same time; and - R 6 is hydrogen: loweralkyl; halo; or OR 4 ; R 2 is where r and s are independently 0 to 3; B is absent; -0-; -S-; or -NR 8 -; where R 8 is hydrogen; loweralkyl; alkanoyll or aroyl; and R 7 is where R 9 is loweralkyl; aralkyl; aryl; heteroaryl; or heteroarloweralkyl; and these groups substituted by hydroxy, lower alkoxy or halo carboxyl; carboxamido; nitromethenyl; R 10 is hydrogen; loweralkyl aryl; or amidino; R 11 is hydrogen: loweralkyl; cyano; amidino: aryl; aroyl; loweralkanoyl; -NO 2 ; -SO 2 NH 2 ; or SO 2 R 13 , R 12 is hydrogen; loweralkyl; halo; aralkyl; amino; cyano; mono-or diloweralkylamino; or OR 4 . R 13 is hydrogen; laweralkyl· or aryl; R 15 is hydrogen; lower alkyl aralkyl; or aryl; constitute a basic heterocycle of 5 or 6 atoms or benzofused analogs thereof and optionally containing 1-3 N atoms, an oxygen, a sulfur, an S=O, or an S0 2 group optionally substituted by amino, lower alkyl amino, diloweralkyl amino, lower alkoxy, or aralkyl groups; R 3 is C 3-8 cycloalkyl and benzofused C 3-8 cycloalkyl; perhydrobenzofused C 3-8 cycloalkyl; aryl; substituted aryl; heteroaryl; substituted heteroaryl; R 14 is hydrogen or loweralkyl; and, a pharmaceutically acceptable salt thereof.

Claim 5

A pharmaceutical composition useful in treating hypertension comprising a pharmaceutically acceptable carrier and an antihypertensively effective amount of a compound of the formulae: and wherein: R and R 2 are independently hydrogen- loweralkyl; aralkyl; or aryl: R 1 is hydrogen; branched or straight chain S 1-12 alkyl and alkenyl; C3 -C 9 cycloalkyl and benzofused alkyl; substituted loweralkyl where the substituents re halo. hydroxy loweralkoxy, aryloxy, amino, mono- or diloweralkylamino, acylamino, arylamino, guanidino, mercapto, loweralkylthio, arylthio, carboxy, carboxamido, or loweralkoxycarbonyl; aryl. substituted aryl where the substituents are loweralkyl, loweralkoxy, or halo; arloweralkyl; arloweralkenyl; heteroarloweralkyl; heteroarloweralkenyl; substituted arloweralkyl, substituted arloweralkenyl, substituted heteroarloweralkyl, or substituted heteroarloweralkenyl where the aryl and heteroaryl substituents are halo, dihalo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl, acylamino, mono- or diloweralkylamino, carboxyl, haloloweralkyl, nitro, cyano, or sulfonamido, and where the loweralkyl portion of arloweralkyl may be substituted by amino, acylamino, or hydroxyl; or where X and Y taken together are CH 2 -CH 2 ; R 4 is hydrogen; loweralkyl aryl; substituted aryl, R 5 is hydrogen; loweralkyl; aryl; or substituted aryl. n is 1 to 3; W is absent; -CH 2 -; or Z is where m is 0 to 2, provided that m may not be 0 and W may not be: absent .at the same time; and - R 6 is hydrogen: loweralkyl; halo; or OR 4 ; R 2 is where r and s are independently 0 to 3; B is absent; -0-; -S-; or -NR 8 -; where R 8 is hydrogen; loweralkyl; alkanoyll or aroyl; and R 7 is where R 9 is loweralkyl; aralkyl; aryl; heteroaryl; or heteroarloweralkyl; and these groups substituted by hydroxy, lower alkoxy or halo carboxyl; carboxamido; nitromethenyl; R 10 is hydrogen; loweralkyl aryl; or amidino; R 11 is hydrogen: loweralkyl; cyano; amidino: aryl; aroyl; loweralkanoyl; -NO 2 ; -SO 2 NH 2 ; or SO 2 R 13 , R 12 is hydrogen; loweralkyl; halo; aralkyl; amino; cyano; mono-or diloweralkylamino; or OR 4 . R 13 is hydrogen; laweralkyl· or aryl; R 15 is hydrogen; lower alkyl aralkyl; or aryl; constitute a basic heterocycle of 5 or 6 atoms or benzofused analogs thereof and optionally containing 1-3 N atoms, an oxygen, a sulfur, an S=O, or an S0 2 group optionally substituted by amino, lower alkyl amino, diloweralkyl amino, lower alkoxy, or aralkyl groups; R 3 is C 3-8 cycloalkyl and benzofused C 3-8 cycloalkyl; perhydrobenzofused C 3-8 cycloalkyl; aryl; substituted aryl; heteroaryl; substituted heteroaryl; R 14 is hydrogen or loweralkyl; and, a pharmaceutically acceptable salt thereof.

Claim 6

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a cbmpound of Claim 1; and, an antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazaide, hydroflumethiazide, indacrinone, metolazone, metoprolol tartate, methylclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol; rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol, trichlormethiazide, trimethophan camsylate, benzthiazide, guinethazone, ticrynafen, triamterene, acetazolamide, aminophylline, cvclothiazide, ethacrynic acid, furosemide, merethoxylline procaine and sodium ethacrynate.

Claim 7

A process for preparing Formulae T and Ia compounds of Claim 1 which comprises derivatization with appropriate reagents of substituted N-carboxymethyl dipeptides having the formulae: and wherein Q is H or and R , R 1 , B, r, s, R 3 and R 4 are as defined in Claim 1 to obtain compounds of Formulae I and Ia and, if desired, removing protecting groups if present by standard methods and, if further desired, preparing salts of said compounds by conventional means.